A. Field Of The Invention
This invention relates to novel compounds of Formula I having a 2,2-di-substituted chromanonyl (benzopyran) ring-structure which are antagonists of leukotriene D.sub.4 (LTD.sub.4) and the slow reacting substance of anaphylaxis (SRS-A). In particular, the compounds of this invention are useful as pharmaceutical agents to prevent or alleviate the symptoms associated with LTD.sub.4, such as allergic reactions and inflammatory conditions.
LTD.sub.4 is a product of the 5-lipoxygenase pathway and is the major active constitutent of slow reacting substance of anaphylaxis (SRS-A), a potent bronchoconstrictor that is released during allergic reactions. See R. A. Lewis and K. F. Austen, Nature, 293, 103-108 (1961). When administered to humans and guinea pigs, LTD.sub.4 causes bronchoconstriction by two mechanisms: (1) directly, by stimulating smooth muscle; and (2) indirectly, through release of thromboxin A.sub.2 which then causes contraction of respiratory smooth muscle. Because antihistamines are ineffective in the management of asthma, SRS-A and not histamine is believed to be a mediator of the bronchoconstriction occurring during an allergic attack. LTD.sub.4 may also be involved in other inflammatory conditions such as rheumatoid arthritis. Furthermore, LTD.sub.4 is a potent coronary vasoconstrictor and influences contractile force in the myocardium and coronary flow rate of the isolated heart. See F. Michelassi, et al., Science, 217, 841 (1982); J. A. Burke, et al., J. Pharmacol. and Exp. Therap., 221, 235 (1982).
B. Prior Art
Appleton, et al., J. Med. Chem., 20, 371-379 (1977) discloses a series of chromone-2-carboxylic acids having a single substituent in the 2-position, which are antagonists of SRS-A. Specifically, sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl -4H-1-benzopyran-2-carboxylate (FPL 55712), appears to be the first reported specific antagonist of SRS-A and LTD.sub.4.
Miyano, et al., (U.S. Pat. No. 4,546,194) discloses substituted chromanon-2-yl alkanols and derivatives thereof which are useful as LTD.sub.4 inhibitors. In Miyano, the LTD.sub.4 inhibitors have two substituents at the two position of their chromane ring, one of which is alkyl. Moreover, Miyano discloses a diether at position 7 which has 4-acetyl-3-hydroxy-2-propylphenoxy as the substitutent at its terminus.
Similar references disclosing chromane compounds which are useful as LTD.sub.4 antagonists are the following: European Patent Application Nos. 0079637, 129,906, and 150,447; U.S. Pat. No. 4,565,882; Japanese patent 60/42378; and C. A. 103(19) 160 389 G.